Isoxazolopyridine ketone derivatives

ABSTRACT

NEW ISOXAZOLO(5,4-B)PYRIDINE-5-KETONES HAVING THE GENERAL FORMULA   3-R1,4-(R2-N(-R3)-),4-(R4-CO-)ISOXAZOLO(5,4-B)PYRIDINE   AS WELL AS THEIR SALTS, ARE USEFUL AS CENTRAL NERVOUS SYSTEM DEPRESSANTS. THESE COMPOUNDS ALSO INCREASE THE INTRACELLULAR CONCENTRATION OF ADENSOINE-3&#39;&#39;,5&#39;&#39;-CYCLIC MONOPHOSPHATE.

United States Patent O'fice 3,736,327 Patented May 29, 1973 3,736,327 ISOXAZOLOPYRIDINE KETONE DERIVATIVES Theodor Denzel, Nuremberg, and Hans Hoeliu, Tegernheim, Germany, assignors to E. R. Squibb & Sons, Inc.,

Princeton, NJ. N Drawing. Filed Mar. 29, 1971, Ser. No. 129,198 Int. Cl. C07d 39/00 U.S. Cl. 260-296 H 7 Claims ABSTRACT GF THE DISCLOSURE New isoxazolo[5,4-b]pyridine-S-ketones having the general formula as well as their salts, are useful as central nervous system depressants. These compounds also increase the in tracellular concentration of adenosine-3',5-cyclic monophosphate.

SUMMARY OF THE INVENTION This invention relates to new isoxaZ0lo[5,4-b]pyridine S-ketone derivatives and salts thereof. These new compounds have the general formula R is hydrogen or lower alkyl. The basic nitrogen group is an acyclic amino moiety wherein R and R each is hydrogen, lower alkyl, phenyl, substituted phenyl (i.e., the phenyl ring contains one or two simple substituents, e.g., a halogen, preferably chlorine, or trifiuoromethyl), phenyl-lower alkylene or di-lower alkylamino-lower alkylene (preferably only one of these).

The basic nitrogen groups may also form a heterocycle of 3-, 5- or 6-members in which an additional nitrogen is present, i.e., the aziridinyl, pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl radicals, each of which may also bear as a substituent a hydroxy-lower alkyl group or one or two lower alkyl groups. R; is alkyl, cycloalkyl, phenyl or substituted phenyl. These radicals may also bear a hydroxy or a hydroxylower alkyl group.

DETAILED DESCRIPTION The symbols have the following meanings in Formula I and throughout this specification.

R is hydrogen or lower alkyl. The basic nitrogen group is an acyclic amino group wherein R and R each is hydrogen, lower alkyl, phenyl, substituted phenyl (i.e., the phenyl ring contains one .or two simple substituents in-. cluding halogen or trifluoromethyl), phenyl-lower 'alkyl ene or di-lower alkylamino lower alkylene (preferably there is only one of these substituents). This basic group may also form a heterocycle of 3-, 5- or 6-members in which an additional nitrogen is present, in particular, aziridinyl, pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl radicals, each of which may also bear as a substituent a hydroXy-lower alkyl group or one or two lower alkyl groups. That is to say, R and R each is hydrogen, lower alkyl, R R -phenyl (wherein R and R each is hydrogen, halogen or trifluoromethyl), phenyl-lower alkylene, or di-lower alkylamino-lower alkylene or R and R together with the nitrogen to which they are attached form one of the heterocyclics mentioned above or the R -mono-substituted or R R disubstituted derivative (wherein R and R are the substituents lower alkyl or hydroxy-lower alkyl in addition to hydrogen).

The lower alkyl and lower alkylene groups in any of the foregoing radicals are straight or branched chain hydrocarbon groups of up to eight carbon atoms like methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. The lowest four members are preferred. Benzyl and phenethyl are the preferred phenyl-lower alkylene groups. All four halogens are included, but chlorine is preferred.

The products of the examples which are representative of the various compounds of this invention constitute preferred embodiments. Most preferably R is hydrogen, particularly when R includes a cyclic substituent or a substituted or unsubstituted acyclic group. Especially preferred compounds of Formula I are those wherein R is methyl, R is butyl, phenyl, substituted phenyl and tertiary amine, R is hydrogen and R is methyl.

The new compounds of Formula I are formed by the following series of reactions. The symbols in the structural formulas have the same meaning as previously described.

A 5-aminoisoxazole of the formula [produced by reacting 3-iminobutyronitrile with hydroxylamine analogous to the procedure described in Ann. Chem. 624, 22 (1959),] is made to react with an alkoxymethyleneaceto-acetic acid ester of the formula (III) COR4 Alkyl-OOH=C COO-alkyl by heating at a temperature of about -l30 C.

The resulting compound of the formula ether at about 230 to about 260 C. while distilling off the alcohol formed, producing a compound of the formula with a hydroxy group in the 4-position.

This 4-hydroxy compound is refluxed for several hours with a phosphorus halide like phosphorus oxychloride to obtain the intermediate of the formula This reaction is effected by treating the reactants either at room or elevated temperature. For some cases it may be advantageous to make use of an autoclave.

The compounds of Formula I form salts which are also part of this invention. The salts include acid-addition salts, particularly the non-toxic, physiologically acceptable members. The bases of Formula I form salts by reaction with a variety of inorganic and organic acids providing acid addition salts including, for example, the hydrohalides (especially the hydrochloride and hydrobromide), sulfate, nitrate, phosphate, oxalate, tartrate, malate, citrate, picrate, acetate, ascorbate, succinate, arylsulfonates like benzenesulfonate and toluenesulfonate, alkanesulfonates like methanesulfonate, cyclohexanesulfouate, cyclohexanesulfamate, etc. The acid addition salts frequently provide a convenient means for isolating the product, e.g., by forming and precipitating the salt in an appropriate menstruum in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of Formula I. Other salts may then be formed from the free base by reaction with an equivalent of acid.

The new compounds of this invention are central nervous system depressants and may be used as tranquilizers or ataractic agents for the relief of amriety and tension states, for example, in mice, cats, rats, dogs and other mammalian species, in the same manner as chlordiazepoxide. For this purpose a compound or mixture of compounds of Formula I, or non-toxic, physiologically acceptable acid addition salt thereof, may be administered orally or parenterally in a conventional dosage form such as tablet, capsule, injectable or the like. A single dose, or preferably 2 to 4 divided daily doses, provided on a basis of about 1 to 50 mg. per kilogram per day, preferably about 2 to 15 mg. per kilogram per day, is appropriate. These may be conventionally formulated in an oral or parenteral dosage form by compounding about 10 to 250 mg. per unit of dosage with conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by accepted pharmaceutical practice.

The new compounds also increase the intracellular concentration of adenosine-3',5-cyclic monophosphate, and thus by the administration of about 1 to 100 mg./l g./day, preferably about 10 to 50 mg./kg., in single or two to four divided doses in conventional oral or parenteral dosage forms such as those described above may be used to alleviate the symptoms of asthma.

The following examples are illustrative of the invention. All temperatures are on the centigrade scale.

. EXAMPLE 1 5-acetyl-4- (n-butylamino) -3-methylisoxazoloF [5 ,4-b] pyridine (a) (S-methyl 5 isoxazolyl)aminomethyleneacetoacetic acid ethyl ester.98 g. of 3 methyl 5 aminoisoxazole (1 mol.) and 186 g. of ethoxymethyleneacetoacetic acid ethyl ester (1 mol.) are heated with stirring for 45 minutes at 130. After this period, ethanol is removed under reduced pressure. The residue solidifies on cooling and is recrystallized from ethanol, M.P. 93-95 yield 208 g. (87%).

(b) S-acetyl 4 hydroxy 3 methylisoxazolo[5,4- b] pyridine.--23.8 g. of (3-methyl 5 isoxazolyDaminomethyleneacetoacetic acid ethyl ester (0.1 mol.) are quickly added to 100 ml. of vigorously refluxing diphenyl ether. After 5 minutes, the reaction mixture is cooled, as rapidly as possible. After addition of 100 ml. diethyl ether, 5-acetyl-4-hydroxy-3-methylisoxazolo- [5,4-b1pyridine crystallizes and is filtered off. Recrystallization from methanol yields 9.5 g. (49.5%) of pure product, M.P. 162.

(c) S-acetyl 4 chloro 3 methylisoxazolo[5,4-b] pyridine-38.4 g. of 5-acetyl 4 hydroxy 3 methylisoxaZolo[5,4-b]pyridine (0.2 mol.) in 100 ml. of phosphorus oxychloride are heated for 5 hours at After this time, the excess phosphorus oxychloride is removed in vacuo and the residue is carefully neutralized with saturated sodium bicarbonate solution. The chloro compound is extracted three times with 100 ml. portions of chloroform. The organic layer is collected, dried over sodium sulfate and the solvent evaporated. The solid residue is recrystallized from petroleum ether. Yield, 33 g. (83%) of 5-acetyl 4 chloro 3 methylisoxazolo- [5,4-b1pyridine, M.P. 63.

(d) 5 acetyl 4 (n-butylamino)-3-methylisoxazolo- {5,4-b]pyridine.--2.1 g of S-acetyl-4-chloro-3-metl1ylisoxazolo[5,4-b]pyridine (0.01 mol.) are added with stirring to 2.2 g. of n-butylamine (0.03 mol.). After 5 minutes the mixture is diluted with 50 ml. water and the 5-acetyl-4- (n-butylamino) -3-methylisoxazolo [5,4-b] pyridine which precipitates is filtered off and recrystallized from petroleum ether, yield 2.2 g. M.P. 1161l7.

The hydrochloride salt is produced by treating the above product with dilute ethanolic hydrogen chloride solution.

By utilizing sec,-butylamine in the procedure of part d, S-acetyl 4 (sec.-butylamino) 3 methylisoxazolo- [5,-4-b1pyridine is obtained, M.P. 79-81.

The following additional products are produced by substituting the appropriately substituted starting material for the 3-methyl 5 aminoisoxazole or ethoxymeth yleneacetoacetic acid ethyl ester in part (a) or butylamine in part (d) of Example 1, respectively:

04H? cyclobutyl cyclopentyl 8 CH; cyelohexyl TABLE-Continued Ex. R R4 Rs 5 9 CH3 CH3 \l 10 H CzHg 11 CH3 CH3 12 CH3 CH: N/ \N 13 CH3 CH: -N:

14 CH3 CH3 N NC2H OH 15 CH: Q -NH;

16....... CH: -NHC4H0 17-...-.- H NHCH:

1 C H C1 19.... C H -NHCH 20 CzHs CF 21 CzHs CzHs H 2 4N(Cz 5)2 22 H CH3 -NHCH2CH 23 H CH: -CH;

--CHs 24 H CH3 CH;

C-Rl

wherein R is hydrogen or lower alkyl R and R each is hydrogen, lower alkyl or R and one of said terms is R -phenyl, phenyl-lower alkylene, dilower alkylamino-lower alkylene or R and R together with the nitrogen to which they are attached form one of the heterocyclics R R -aziridinyl, R R -pyrrolidino, R is lower alkyl, cyclo-lower alkyl, phenyl, hydroxyphenyl or hydroXy-lower alkylphenyl, R is hydrogen, R is hydrogen, halogen or trifiuoromethyl and R and R each is hydrogen or lower alkyl providing only one of said R and R is R R -phenyl, phenyl-lower alkylene or di-lower alkylamino-lower alkylene,

and physiologically acceptable acid addition salts thereof. 2. A compound as in claim 1 wherein R R R and R each is lower alkyl.

3. A compound as in claim 1 wherein R is hydrogen,

and R R and R each is lower alkyl.

4. A compound as in claim 3 wherein R and R each is methyl and R is butyl.

5. The acid addition salt of compound of claim 4. 6. A compound as in claim 1 wherein R is hydrogen,

R is lower alkyl and the group is pyrrolidino.

7. A compound as in claim 6 wherein the lower alkyl group is ethyl.

References Cited UNITED STATES PATENTS 3,381,016 4/1968 Markillie 260-296 H 3,541,101 11/1970 Markillie 260--288 OTHER REFERENCES Roberts et 211., Basic Principles of Organic Chemistry, Benjamin Publishers, pp. 561 and 806; QD 251 R58 0.6 (1965).

ALAN L. ROTMAN, Primary Examiner U.S. Cl. X.R.

260-250 A, 256.4 R, 268 BC, 293.58, 294.8 C, 295.5 S; 424250, 251, 263, 267

Po-ww UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,736, 327 Dated Me 29, 19 7} Invenrofls) I i Q l It is certified that error appears in the above-identified patent and that said Letters Patent; are hereby corrected as ehown below:

Claim 1, line after the formula cancel --R and--:'

line 3, after the formula before R insert ,1.

si ned and Sealed this 1mm d ayof May 1971;.

(SEAL) I At-test I EDWARD M.FLETCHER,JR. j CQ AESEALL DANN Attesting Officer I Commissioner of Eatents 

